tbuckley/cabot-search huggingface dataset:
Development and assessment of the effectiveness of an LGBT cultural sensitivity training for oncologists: The COLORS training.
Authors: Matthew B. Schabath, Jaileene Perez-Morales, Eryk N. Hernandez, Jarred D. Miller, Julia Seay, Gwendolyn P. Quinn
Journal: Journal of Clinical Oncology (2022)

11000 Background: Published studies report oncologists have limited knowledge about LGBT health and cancer needs but also report high interest in receiving education regarding the unique health needs of LGBT patients with cancer. As such, our group developed the Curriculum for Oncologists on LGBT populations to Optimize Relevance and Skills (COLORS), an interactive web-based LGBT cultural sensitivity training for oncologists that focused on focused on improving knowledge and communication skill-building. We report here on the results from two single-arm feasibility/acceptability trials and one randomized pragmatic trial (RPT) demonstrating effectiveness of the COLORS training. Methods: The first single-arm trial included 44 oncologists from three cancer centers in Florida and the second single-arm trial included 50 oncology fellows recruited through ASCO. The RPT included 225 oncologists randomly selected for equal distribution across the U.S., and participants were randomly assigned to either the COLORS training or a publicly available, web-based LGBT comparison training. Each of these studies included pre- and post-training assessments of LGBT-related knowledge, attitudes, and affirming practices. The RCT included a 3-month follow-up assessment to gauge retention of LGBT-affirming knowledge, attitudes, and practices over time. Results: Both single arm trials demonstrated that the COLORS training was feasible, acceptable, and results from the pre- and post-training assessments suggested the training improved knowledge, attitudes, and affirming practice behaviors. In the RPT, those randomized to COLORS demonstrated significant improvements in LGBT-related attitudes pre- to post-training (p &lt; 0.01), and no significant changes in attitudes were observed among those randomized to the comparison training (p = 0.98). Both trainings yielded significant (p &lt; 0.01) increases from pre- to post-training in LGBT-affirming practice behaviors. Likewise, both trainings yielded significant (p &lt; 0.01) improvements in knowledge from pre- to post-training. Similar significant findings were observed when we analyzed the 3-month follow-up assessment. Conclusions: Results from the prior single-arm trials and the current RCT demonstrate that the COLORS training is effective in improving oncologist knowledge, attitudes, and affirming clinical practices related to the care of LGBT patients with cancer. Part of this work was funded by the Bristol Myers Squibb (BMS) Foundation and BMS Company.
Final analysis of the phase 1b/2 study of sabizabulin in men with metastatic castration-resistant prostate cancer who progressed on an androgen receptor targeting agent.
Authors: Mark Christopher Markowski, Mario A. Eisenberger, Christopher Michael Pieczonka, Robert H. Getzenberg, Domingo Rodriguez, K. Gary Barnette, Mitchell S. Steiner, Daniel R. Saltzstein, Emmanuel S. Antonarakis, Ronald F. Tutrone
Journal: Journal of Clinical Oncology (2022)

5049 Background: Sabizabulin is a novel oral cytoskeleton disruptor being developed for use in metastatic castration resistant prostate cancer (mCRPC). A Phase 1b/2 clinical study was conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC resistant to androgen receptor targeting agents. Methods: The Phase 1b portion of the study in 39 men utilized escalating and expanding dose and duration. The Phase 2 portion studied 41 men with mCRPC at the recommended Phase 2 dose of 63 mg daily. Efficacy was assessed by bone/CT scans. A final analysis of the safety and efficacy data including the primary endpoint, the median progression-free survival was conducted. Results: Although the MTD was not reached in the Phase 1b, the recommended Phase 2 dose was set at 63 mg/day to maximize GI tolerability. The most common adverse events (&gt; 10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 data) were predominantly Grade 1-2. Grade ³3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle (21 days) of 63 mg or higher (n = 55) included an objective response rate of 6/29 (20.7%) in patients with measurable disease (1 complete, 5 partial). 14/48 (29.2%) of the patients had PSA declines. The Kaplan-Meier median radiographic progression-free survival was estimated to be 11.4 months (95% C.I. 29.63-65.79) (n = 55). Durable responses lasting &gt; 2.75 years were observed with 14.5% (8/55) demonstrating a response greater than 12 months. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with significant preliminary cytotoxic and cytostatic antitumor activity. These data support the ongoing Phase 3 VERACITY trial of sabizabulin in men with mCRPC who have progressed on an androgen receptor targeting agent. Clinical trial information: NCT03752099.
Patient-reported outcomes from the GARNET trial in patients with advanced or recurrent mismatch repair deficient (dMMR) colorectal cancer (CRC): A post hoc subgroup analysis.
Authors: Jennifer Hanlon, Jennifer Taylor Veneris, Susan Boklage
Journal: Journal of Clinical Oncology (2022)

3558 Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as a monotherapy in patients (pts) with dMMR advanced/recurrent endometrial cancer that has progressed on or after prior treatment with a platinum-containing regimen or in pts with dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. Here we report on patient-reported outcomes (PROs) in pts with dMMR CRC, a post hoc subgroup analysis. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort F enrolled pts with dMMR/microsatellite instabilityhigh or POLε-mutated non-endometrial solid tumors. Pts with CRC must have received prior fluoropyrimidine, oxaliplatin, and irinotecan. Pts received 500 mg of IV dostarlimab Q3W for 4 cycles, then 1000 mg Q6W until discontinuation. PRO assessment, an exploratory endpoint, was measured using the EORTC-QLQ-C30. PROs were collected at baseline, at each dose cycle, and after discontinuation. Multi-item and item-level analyses were collected and scored; improvement was defined as mean change from baseline (directional change dependent on item). A 10-pt change in mean from baseline was considered clinically significant for the analysis. Results: PRO data at baseline were available for 96 pts with CRC who received ≥1 dose of dostarlimab. Improvements from baseline for quality of life (QOL) and most gastrointestinal symptom scales were observed and maintained from cycle 2 through 7 (Table). Stability in diarrhea was seen from cycles 2 through 7. Conclusions: PROs from the GARNET trial in pts with dMMR CRC show that QOL and disease-related gastrointestinal symptoms were improved or maintained while on dostarlimab treatment. These data, with the previously reported efficacy and safety profile, support the use of dostarlimab in pts with dMMR CRC. Clinical trial information: NCT02715284. [Table: see text]
<i>FGFR2</i> fusion detection in plasma: A new era in the clinical monitoring of iCCA.
Authors: Alberto Gonzalez-Medina, Helena Verdaguer, Maria Vila-Casadesús, Alexandre Sierra, Gloria Castillo, Carles Fabregat-Franco, Marina Gómez-Rey, Josep Maria Miquel Aymar, Teresa Macarulla, Ana Vivancos
Journal: Journal of Clinical Oncology (2022)

4085 Background: Actionable genetic alterations can be identified in over 50% of intrahepatic cholangiocarcinoma (iCCA). Since EMA approved Pemigatinib, a selective Fibroblast growth factor receptor 1-3 (FGFR1-3) inhibitor for the treatment of CCA with FGFR2 fusions or rearrangements, the screening of patients who may benefit from such targeted therapies is especially relevant. In addition, novel FGFR inhibitors that are effective for treatment of resistant mutant clones are under development. In patients with no available tissue for genomic profiling or at different timepoints after targeted therapy, NGS testing of circulating cell-free DNA (ccfDNA) would be the most convenient option. Hence, two important issues must be addressed: i) technical set-up and validation of detection of FGFR2 rearrangements in plasma, and ii) patient shedding in iCCA, in order to consider liquid biopsy for routine clinical care. Methods: We conducted a retrospective study in a cohort of 18 iCCA patients with known FGFR2 fusion or rearrangement events previously identified in tumor FFPE by NGS (FoundationOne CDx test). A custom-designed capture-based NGS panel for use in plasma or tissue (VHIO-iCCA test) was developed to detect FGFR2 rearrangements and other common altered genes in iCCA. After validating our VHIO-iCCA panel with fusion positive FFPE samples, a concordance study was conducted to evaluate the detection of FGFR2 fusion and rearrangements in matched-to-tissue timepoint plasmas. Finally, additional serial plasma samples taken during FGFR inhibitor treatment were also analyzed. Results: From the 18 rearrangement events previously detected with FoundationOne CDx, we were able to identify all 18 in FFPE samples and 15 in the paired plasma using our VHIO-iCCA panel, representing a 100% and 83% concordance, respectively. In the 3 discordant cases, no additional alterations were detected in plasma, indicating a lack of circulating tumor DNA (ctDNA) shedding. Serial sampling of these patients indicated persistent non-shedding. The analysis of fusion allele fraction (FAF) in serial plasma samples revealed that detection of fusion FGFR2 changed during treatment and correlated with best response. In general, patients with a stable FAF showed a SD, while patients which reduced FAF presented a PR. Conclusions: This extremely valuable set of cases has allowed us to validate our VHIO-iCCA panel to be used in tissue and plasma, and to determine that the sensitivity in plasma is &gt;80%, making this a feasible option to avoid tissue biopsies, whenever patients cannot undergo the procedure and even to aid in cancer monitoring. Patient shedding is high in iCCA, yet a fraction of patients may not find a useful resource in liquid biopsy. For those who shed ctDNA, monitoring through the FAF may guide clinical management of iCCA.
Multifactorial drug response modeling based on cancer organoid data.
Authors: Yitan Zhu, Thomas S. Brettin, Alexander Partin, Fangfang Xia, Maulik Shukla, Hyunseung Yoo, Andrea Cancino, Brian Larsen, Jenna Shaxted, Ameen Salahudeen, Kevin White, Rick L. Stevens
Journal: Journal of Clinical Oncology (2022)

e13544 Background: Prediction of drug response based on cancer molecular profiles is of paramount importance for precision oncology. Most existing drug response prediction models are built using drug screening data of immortalized cancer cell lines, which usually have altered genomic profiles compared with patient tumors. Recently, patient-derived organoids (PDOs) are emerging as a promising platform better representing patient tumors. We build computational drug response prediction models based on PDO drug screening data, which is the first study of its type to our knowledge. Methods: We successfully developed 27 PDO lines of colorectal cancer and 20 PDO lines of head and neck (H&amp;N) cancer. Transcriptomics, copy number variation (CNV), and targeted DNA mutation data were generated for the PDO lines. The PDO lines were screened with 36 drugs of diversified mechanisms. The area under the dose response curve was taken as the response measurement. We used the LightGBM algorithm to build response prediction models based on cancer molecular data and drug chemical descriptors/fingerprints. To investigate the influence of different factors on the prediction performance, including different cancer types, cancer molecular features, drug features, data preprocessing methods, and others, we applied a multifactorial analysis scenario to build and evaluate 3,384 prediction models constructed with all possible combinations of the factors. For example, we built prediction models for H&amp;N and colorectal PDOs separately and jointly. Results: A prediction model built for H&amp;N PDOs achieved the highest prediction performance among all prediction models, which was R 2 of 0.790 in 10-fold cross-validation. The model was built using drug descriptors, CNVs, and expressions of “landmark” genes well-representing cellular transcriptomic changes identified in the LINCS project. The table below includes all the factorial differences that caused an average R 2 change larger than 1%. All R 2 changes are statistically significant (p-values &lt; 1×10 –50 ), evaluated by pair-wise t-tests comparing models built with the status of the factor changed. The prediction performance increased, from colorectal cancer to two cancer types combined, and to H&amp;N cancer. Gene expression data, either whole-transcriptome or the subset of LINCS genes, boosted the prediction performance. Between the two different dyes used to stain dead cells, TO-PRO-3 provided a higher prediction performance than Caspase-3/7. Conclusions: The highest drug response prediction performance achieved is R 2 of 0.790. Cancer type, dye, and whether gene expressions are used in modeling are the factors most influential on prediction performance.[Table: see text]
A first-in-human, multicenter, phase 1/2, open-label study of XTX202, a masked and tumor-selective recombinant human interleukin-2 (IL-2) protein, in patients with advanced solid tumors.
Authors: Meredith McKean, John D. Powderly, Meghan Duncan, Teleen Norman, Ekta Patel, Jennifer O'Neil, George Lee, Katarina Luptakova, Howard E. Kaufman
Journal: Journal of Clinical Oncology (2022)

TPS2697 Background: High-dose interleukin-2 (IL-2) has been approved in metastatic renal cell carcinoma (RCC) and metastatic melanoma, and can result in durable complete responses, including cures. Its use has been limited by life-threatening treatment-related multisystem toxicities, consisting mainly of vascular leak syndrome. XTX202 is a masked, tumor-selective IL-2 that is designed to be pharmacologically inactive in non-tumor tissue when circulating systemically and unmasked by matrix metalloproteases (MMPs) found preferentially in the tumor microenvironment (TME). XTX202 is expected, therefore, to achieve a wider therapeutic index resulting in increased efficacy and lower toxicity compared to existing non-tumor selective IL-2 based-therapies. The IL-2 domain of the XTX202 molecule is modified to reduce binding to the high-affinity IL-2 receptor while maintaining binding to the intermediate-affinity IL-2 receptor, thereby decreasing activation of regulatory T-cells relative to wild-type IL-2, while still activating effector T cells. A masking domain is designed to pharmacologically inactivate IL-2 until it is activated by MMPs that are enriched in the TME. Cleavage at a protease cleavage site in the XTX202 linker by MMPs results in an active IL-2 moiety when the masking domain is released. XTX202 is designed with the goal of producing a localized anti-tumor immune response and limiting exposure of the active form of XTX202 in non-tumor tissue. Preclinically, XTX202 exhibited tumor-selective activity in mice without peripheral toxicities in non-human primates [O’Neil et al. ASCO 2021]. Methods: XTX202-01 trial (NCT05052268) is a first-in-human Phase 1/2 study to determine a recommended Phase 2 dose of XTX202 (Phase 1) and to evaluate the efficacy of XTX202 monotherapy in patients with metastatic RCC and unresectable or metastatic melanoma (Phase 2). Patients with advanced solid tumors are eligible for Phase 1 and will receive XTX202 monotherapy administered every 21 days in an accelerated and standard 3+3 dose escalation design. Phase 2 will consist of 2 parts: Part 2a will enroll patients with metastatic RCC who have received a prior tyrosine kinase inhibitor therapy and have been treated and progressed on an anti-PD-1 therapy. Part 2b will enroll patients with unresectable or metastatic melanoma who have received immune-checkpoint therapy with an anti-PD-1 therapy and an anti-CTLA-4 therapy to determine the efficacy of XTX202 monotherapy in this population. Enrollment to the study began in January 2022. Clinical trial information: NCT05052268.
Primary site and survival in ewing sarcoma: A National Cancer Database (NCDB) analysis.
Authors: Connor Tupper, Peter T. Silberstein, Vincent Eaton
Journal: Journal of Clinical Oncology (2022)

e23510 Background: Ewing sarcoma is the one of the most common primary malignancies of bone, with an incidence of about 1 case per million in the United States. Ewing sarcoma typically affects the pelvis, axial skeleton, and femur. However, this cancer can affect other bony regions and, to the author’s knowledge, all possible primary sites have not been investigated in-depth in regards to tumor location and the effect it may have on outcomes. The aim of this study is to conduct such an investigation to see whether or not the primary site of the tumor in osteosarcoma patients may have an effect on survival. Methods: Using the NCDB, patients diagnosed with Ewing sarcoma between 2004-2018 were identified using ICD-O-3 histology code 9260. The cohort was analyzed to investigate survival outcomes in different primary sites. Univariate analysis was then performed assessing patient length of survival for each primary site subtype. Data was analyzed using SPSS and statistical significance was set at α = 0.05. Results: A total of 4284 patients with known primary site that had survival data were included. The sites with the best survival were the skull, face, and mandible and upper limb. Patients with primary tumor of the skull, face, and mandible survived significantly longer than all groups other than the upper limb (all p &lt; .01). Upper limb patients survived significantly longer than all groups other than the skull, face, and mandible and lower limb (all p &lt; .05). The labeled primary site with the lowest survival was the pelvis, sacrum, and coccyx and significantly lower than the lower limb, vertebral column, and ribs, sternum, and clavicle (all p &lt; .01). Survival of patients with primary site of the upper limb versus lower limb, and vertebral column versus ribs, sternum, and clavicle did not differ (each p &gt; .05). Conclusions: This study found numerous survival differences between patients diagnosed with Ewing sarcoma of different primary sites. Labeled primary sites of the skull, face, and mandible and upper limb were associated with best survival while the pelvis, sacrum, and coccyx were associated with worst survival. Future studies may benefit from investigations into variables that may impact the survival differences we have presented including staging, treatments, time from diagnosis to treatment, and insurance status.[Table: see text]
Phase II multicentric Italian trial on repositioning of the antipsychotic drug chlorpromazine and its combination with temozolomide in patients with MGMT unmethylated glioblastoma: The RACTAC trial.
Authors: Giuseppe Lombardi, Marco Giorgio Paggi, Silvia Matteoni, Veronica Villani, Dario Benincasa, Claudia Abbruzzese, Giulia Cerretti, Marta Padovan, Mario Caccese, Antonio Silvani, Andrea Pace
Journal: Journal of Clinical Oncology (2022)

TPS2073 Background: The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. Methods: With these assumptions, we started a multicentric single arm Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol after radiochemotherapy combination. CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 38 patients out of 41 patients planned have been enrolled. Clinical trial information: NCT04224441.
Mutational profiles of sporadic synchronous colorectal cancer.
Authors: Lu-Ping Yang, Teng-Jia Jiang, Ming-ming He, Qi Zhao, Yihong Ling, Zi-xian Wang, Hao-Xiang Wu, Ying Jin, Zhen Zhang, Rui-hua Xu, Feng Wang
Journal: Journal of Clinical Oncology (2022)

e15555 Background: Synchronous colorectal cancer (SCRC) refers to a special group of CRC with at least two primary tumors detected simultaneously in one patient, with 90% being sporadic. Although the systemic treatments of late-stage SCRC are mainly based on the molecular testing of one primary lesion, this might not be representable of the other tumors and metastatic lesions. This study aimed to investigate the molecular features and genetic heterogeneity of sporadic SCRC in order to guide clinical practice. Methods: We retrospectively collected all the primary tumor samples of 51 patients with sporadic SCRC, profiled 103 samples with whole-exome sequencing, and analyzed their molecular landscape and genomic profiles. We conducted comparative analyses between tumor pairs in one patient, and as well as between SCRC and solitary CRC. The evolutionary dynamics of SCRC tumors was also analyzed. Results: Most gene mutations and copy number variations were inconsistent in paired tumors except for early driving genes APC, TP53 and KRAS. No pathogenic germline variants of familial CRC-related genes were observed . Clonal composition analysis showed that tumors in 94.2% (48/51) of patients with SCRC were genetically heterogeneous. Only 7.8% (4/51) of patients harbored origin-shared tumors. Inconsistent MSI and TMB status were observed in 11.8% (6/51) of patients. For actionable RAS/ BRAF gene loci, 43.1% (22/51) of patients harbored tumor pairs sharing the same wild or mutant status. When compared with solitary CRC, SCRC had higher prevalence of MSI-H (29.4% vs. 12.0-17.0%) or TMB-H (33.3% vs. 10.0-16.0%) and lower mutational frequencies in the RTK/RAS (51.5% vs. 76.1%), PI3K (26.2% vs. 43.4%) and cell-cycle (2.9% vs. 10.2%) oncogenic signaling pathways. Moreover, neutral evolution analysis showed that 84.3% (43/51) of patients had at least one neutral tumor and 45.1% (23/51) of patients had tumors evolving differently. Conclusions: Sporadic SCRC was a special subclass of CRC, featured by prominent TMB-H, dMMR-related signatures, and intertumoral genetic heterogeneity. The tumors from the same SCRC patient tended to have different origins and evolved differently. Thus, clinical treatment strategies for sporadic SCRC should be re-evaluated accordingly.